Acetic acid derivatives as hypolipidemics

ABSTRACT

This disclosure relates to halo-substituted diphenoxyacetic acid amides and to the use of such compounds as hypolipidemics, e.g., the novel compound bis)p-iodophenoxy) acetic acid amide and the known compound bis(p-chlorophenoxy) acetic acid amide.

United States Patent Griot Jan. 30, 1973 [54] ACETIC ACID DERIVATIVES AS [56] References Cited HYPOLIPIDEMICS UNITED STATES PATENTS 1 lnvemo" Rudolf Grim, Richer, Baselland, 3,325,488 6/1967 Lafon ..424/24s x Switzerland 2,954,400 9/1960 Shapiro et al ..424/324 x [73] Assigneez sandobwander Inc" Hanover NJ 3,08l,302 3/1963 Shapiro et al ..424/324 X Filed: April 29, 1970 Primary ExaminerStanley J. Friedman [21] APPL No: 33,045 Assistant ExaminerNorman A. Drezin Attorney-Gerald D. Sharkin, Frederick H, Weinfeldt, Related US. Application Data Robert S. Honor, Walter F. Jewell and Richard E. Vila [63] Continuation-impart of Ser. No. 734,226, June 4, I

1968, abandoned. [57] ABSTRACT This disclosure relates to halo-substituted diphenox- (g1 Rafi/7:733 yacefic acid amides and to the use of Such compounds 58 Field of Search ..424/324 as hypmp'demm the novel compound iodophenoxy) acetic acid amide and the known compound bis(p-chlorophenoxy) acetic acid amide.

5 Claims, N0 Drawings where each of R R R and R independently, represents a hydrogen atom or a halogen atom having an atomic weight of from 35 to I27, i.e., chloro, bromo, or iodo, provided that at least one of R and R is other than H.

The compounds of formula (I) where all the substituents are chloro or where RI and R are both chloro and R and R are both hydrogen atoms are known (U.S. Pat. No. 3,325,488) and the present invention only contemplates the novel use of such compounds. The remaining compounds of formula I are novel and may be prepared in a manner analogous to that known for the preparation of the known compounds. As will be readily appreciated by persons skilled in the art,

when a compound I wherein the two aryloxy radicals are unlike, is desired, such compounds are obtainable in known conventional manner, e.g., by first reacting one equivalent of an appropriate sodium phenolate with two equivalents of methyl dichloroacetate, brominating the resulting product, e.g., with bromine, to obtain the corresponding mono-aryloxyalphabromo-acetate, which is then reacted with one equivalent of a sodium phenolate appropriate for the second aryloxy radical.

As previously indicated, the compounds of formula (I) are useful as hypolipidemics, e.g., hypocholesteremics or hypotriglyceridemics, as in dicated by the effect in rats orally fed'a diet containing active compound ad libitum for days and tested by extracting serum or plasma obtained under hexobarvide elegant and palatable, preparations. Tablets may.

contain the active ingredient in admixture with conventional pharmaceutically acceptable excipients, e.g.,

inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents,

e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption inthe gastro-intestinal tract and thereby provide a sustained action over a longer period. Similarly, suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate), wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate) and preservatives (ethyl-p-hydroxybenzoate). Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin. The injectable compositions are formulated as known in the art and may contain appropriate dispersing or wetting agents and suspending agents identical or similar to those mentioned above. These pharmaceutical preparations may contain about 10-90 percent of the active ingredient in combination with the carrier or adjuvant.

The dosage of active ingredient employed for treatment of hyperlipemia may vary depending on the particular compound employed and the severity of the condition being treated.- However, in general, satisfactory results are obtained when the compounds (I) are administered at a daily dosage of from about 1.0 milligram to 25 milligrams per kilogram of animal body weight for'small mammals, i.e., of less than about 10 kilograms of body weight, and from about 1.0 milligram to 5 milligrams per kilogram of body weight for larger mammals, i.e., having more than 10 kilograms of body weight, preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals, e.g., having a weight of from about 10 to l 00 kilograms, the total daily dosage is from about 10 to 200 milligrams, preferably from about 50 to milligrams. Dosage forms suitable for internal use comprise from about 2.5 to 50 milligrams of the active compound.

The preferred pharmaceutical compositions from the standpoint of preparation and ease of administration are solid compositions, particularly hard-filled capsules and tablets containing from about 2.5 to 50 milligrams of the active ingredient.

The following examples are provided for the purpose of illustration and not by way of limitation. They are not intended so as to limit the scope of the invention.

EXAMPLE 1 Tablets 7,

Tablets suitable for oral administration which contain the following ingredients may be prepared by conventional tabletting techniques. Such tablets are useful in treating hyperlipemia at a dose of one tablet 2 to 4 times a day.

EXAMPLE 2 Dry Filled Capsules Capsules suitable for oral administration which contain the following ingredients are prepared in a conventional manner. Such capsules are useful in treating hyperlipemia at a dose of one capsule 2 to 4 times a day.

ingredient Weight (mg) bis(2.4-dichlorophenoxy)acetic acid amide 25 inert solid diluent (starch, lactose, kaolin) 325 1. A method for treating hyperiipemia in a mammal where each of R and R independently, represents a halogen atom having an atomic weight of from 35 to 127', and each of R, and R independently, represents a hydrogen atom or a halogen atom having an atomic weight of from 35 to 127; at a daily dosage of from about l0 milligrams to 200 milligrams.

2. A method according to claim 1 wherein the compound is bis'( p-chlorophenoxy)acetic acid amide.

3. A method according to claim 1 wherein the compound is bis(p-iodophenoxy)acetic acid amide.

4. A method according to'claim 1 wherein the compound is bis(p-bromophenoxy)acetic acid amide.

5. A method according to claim 1 wherein the compound is bis(2,4-dichlorophenoxy)acetic acid amide.

O CHiL-NH: 

1. A method for treating hyperlipemia in a mammal comprising lowering the blood serum lipid level of a mammal in need of said treatment by orally aDministering to said mammal a compound of the formula:
 2. A method according to claim 1 wherein the compound is bis(p-chlorophenoxy)acetic acid amide.
 3. A method according to claim 1 wherein the compound is bis(p-iodophenoxy)acetic acid amide.
 4. A method according to claim 1 wherein the compound is bis(p-bromophenoxy)acetic acid amide. 